The main objective of this study is to provide the direct and indirect evidences for the role of nerve growth factor (NGF) and its receptor system (NGF-R) in the pathogenesis of psoriasis and psoriatic arthritis (PsA). A role of neurogenic inflammation in psoriasis is suggested by proliferation of lesional cutaneous nerves, upregulation of neuropeptides, and clearance of psoriasis at the sites of anesthesia. Psoriatic keratinocytes (KC) express high level of NGF/NGF-R and NGF is mitogeic to KC. In the SCID mouse-psoriasis model, NGF antibody and K252a (NGF-R/TrkA inhibitor) improve psoriasis. Our preliminary data indicate that compared to rheumatoid arthritis (RA) and osteoarthritis (OA), the synovium of PsA is rich in NGF; major source of NGF is FLS; TrkA is upregulated in FLS, endothelial cells and activated T cells; NGF regulates both activation and survival of CD4+/CD8+ T cells. Thus, similar to psoriatic plaque, NGF/NGF-R may play a contributing role in the pathogenesis of PsA. To substantiate a direct regulatory role of NGF/NGF-R in psoriatic disease we will investigate whether injection of NGF and NGF activated autologus T lymphocytes induce psoriasis in nonlesional skin transplant in the SCID mouse-human skin xenograft model. NGF alone (n=15) and NGF activated autologous CD4+ (n=15) and CD8+ (n=15) T cells will be injected intradermally into the nonlesional psoriatic grafts. In the second group NGF activated CD4+ (n=15) and CD8+ (n=15) cells will be injected intravenously in the tail vein. Controls will be nonlesional psoriasis skin xenografts injected intradermally with unactivated autologous CD4+ (n=10) and CD8+ (n=10) T cells. Another set of controls will be skin grafts from healthy subjects injected with NGF activated autologous CD4+ (n=10) and CD8+ (n=10) T cells. Induction of psoriasis will be confirmed by identifying clinical, histopathological and immunological characteristics of psoriatic lesion. Blood, synovial fluid (SF) and synovial tissues of PsA (n=25) and controls [OA (n=20) and RA (n=10)] will also be examined to identify an immunoregulatory role of NGF/NGF-R on PBMC and SF derived activated memory T cells. The effect of NGF/NGF-R on activation, survival and homing of T cell will be assessed by Hi-D FACS analyses. The regulatory role of NGF on synovial tissue pathophysiology will be elucidated by examining the effect of NGF/NGF-R on proliferation and apoptosis of FLS. RELEVANCE TO VA PATIENT POPULATION: Psoriatic disease is a major morbidity among the VA patient population with profound social and economic impacts. The goal of this study is to understand the pathogenesis of psoriatic disease with an aim to develop better patient care. This study may provide a platform to develop novel therapeutic approach for psoriatic disease by targeting NGF/NGF-R system. PUBLIC HEALTH RELEVANCE: Psoriasis is a disease with flakey skin, and can be associated with arthritis of joints of hands, wrist, feet, ankle, knee, and spine. Nearly 2% of American population has psoriasis and 8-10% of psoriasis patients develop psoriatic arthritis. Psoriasis and psoriatic arthritis are life long chronic debilitating disease. A large number of the VA patient population suffers from these diseases. Cause of psoriatic arthritis is not known, treatment options for psoriatic arthritis are limited and worldwide only a few investigators are doing research to understand the disease process of psoriatic arthritis. In this proposed research project we will be investigating the role of nerve growth factor (NGF) in the disease process of psoriasis and psoriatic arthritis. NGF is a chemical mainly helps in to grow nerves in the embryo. NGF also irritates skin and other human body parts; in scientific language this is called inflammation. NGF is produced by skin cells and joint cells (synovial cells) and many other cells. NGF has a contributing role in several diseases including psoriasis. In this study we are doing a very important research work to find out how NGF causes psoriasis, induces inflammation and pain in psoriatic arthritis. Here we will transplant uninvolved skin from psoriasis patients and skin of normal healthy subjects to immune deficient mouse. We will collect blood cells from psoriasis patients and healthy subjects; we will treat these blood cells with NGF. These NGF treated cells will be injected into the transplanted human skin on mice. We expect that the injection of NGF treated blood cells from psoriasis patients will create psoriasis only in the mice transplanted with skin from psoriasis patients. Thus these experiments may help us to understand whether blood cells and NGF are responsible for causing psoriasis. Currently we are determining whether joint tissues from psoriatic arthritis has increased level of NGF and whether NGF is damaging the joint by altering the immune system. To determine these goals we are studying blood, joint fluid and joint tissues from patients with psoriatic arthritis and other forms of arthritis such as rheumatoid arthritis and osteoarthritis. Our initial results suggest that joint fluid of psoriatic arthritis has more NGF compared to rheumatoid arthritis and osteoarthritis. We have also noticed that NGF is likely activating a special group of immune cells (T lymphocytes) in the joint. It is possible that increased level of NGF and the hyperactive T cells have a contributing role to cause the joint inflammation. In a very recent animal experiment we have demonstrated that psoriasis can be treated by medicines which can neutralize the inflammatory effect of NGF. It is possible to develop nontoxic and effective medicines by neutralizing the bad effects of NGF. Our research work will help to understand the cause of psoriatic disease and thus to develop better patient care and treatment of psoriasis and arthritis. The success of this project will help the VA patient population immensely because both psoriasis and arthritis related sickness is a major problem among this group of patients.